Studies on the occurence and effects of human papillomavirus in tumors of the head and neck

Abstract: The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.

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